Low dietary inorganic phosphate affects the brain by controlling apoptosis, cell cycle and protein translation

Abstract

Inorganic phosphate (P-i) plays a key role in diverse physiologic functions. In a previous study, we showed that high dietary P-i perturbs brain growth through Akt/ERK signaling in developing mice. However, no study has investigated the response of the brain to low dietary P-i. In this study, we addressed this question by studying the effects of low dietary P-i on the cerebrum of developing mice. Two-week-old weaned mice were fed with a low phosphate diet for 4 weeks. At the end of the study, their cerebrum was dissected and signals important for protein translation, apoptosis and cell cycle were examined. The low phosphate diet did not cause physiologically significant changes; it increased the protein expression of phosphatase and tensin homolog deleted on chromosome 10 but decreased Akt activity. In addition, expression of eukaryotic translation initiation factor binding protein coupled with increased complex formation of eukaryotic translation initiation factor 4E/eukaryotic translation initiation factor binding protein I was induced in the cerebrum by low phosphate, leading to reduced cap-dependent protein translation. Finally, low phosphate facilitated apoptosis and suppressed signals important for the cell cycle in the cerebrum of dual-luciferase reporter mice. In summary, our results showed that a low phosphate diet affects the brain by controlling protein translation, apoptosis and cell cycle in developing mice. Our results support the hypothesis that P-i works as a stimulus capable of increasing or decreasing several pivotal genes for normal development and suggest that regulation of P-i consumption is important in maintaining a healthy life. (c) 2008 Elsevier Inc. All rights reserved.